Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses

Tianxiao Huan; Jian Rong; Kahraman Tanriverdi; Qingying Meng; Anindya Bhattacharya; David D McManus; Roby Joehanes; Themistocles L Assimes; Ruth McPherson; Nilesh J Samani; Jeanette Erdmann; Heribert Schunkert; Paul Courchesne; Peter J Munson; Andrew D Johnson; Christopher J O'Donnell; Bin Zhang; Martin G Larson; Jane E Freedman; Daniel Levy; Xia Yang

doi:10.1161/ATVBAHA.114.305176

Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses

Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):1011-21. doi: 10.1161/ATVBAHA.114.305176. Epub 2015 Feb 5.

Authors

Tianxiao Huan¹, Jian Rong¹, Kahraman Tanriverdi¹, Qingying Meng¹, Anindya Bhattacharya¹, David D McManus¹, Roby Joehanes¹, Themistocles L Assimes¹, Ruth McPherson¹, Nilesh J Samani¹, Jeanette Erdmann¹, Heribert Schunkert¹, Paul Courchesne¹, Peter J Munson¹, Andrew D Johnson¹, Christopher J O'Donnell¹, Bin Zhang¹, Martin G Larson¹, Jane E Freedman², Daniel Levy¹, Xia Yang¹

Affiliations

¹ From the National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (T.H., R.J., P.C., A.D.J., C.J.O., D.L.); The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (T.H., R.J., P.C., D.L.); Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (A.D.J., C.J.O.); Department of Mathematics and Statistics, Boston University, MA (J.R., M.G.L.); Department of Medicine, University of Massachusetts Medical School, Worcester (K.T., D.D.M., J.E.F.); Department of Integrative Biology and Physiology, University of California, Los Angeles (Q.M., A.B., X.Y.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M); Department of Medicine, Harvard Medical School, Harvard University, Boston, MA (R.J.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.); Departments of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario, Canada (R.M.); Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom; Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (J.E.); DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (J.E.); Deutsches Herzzentrum München, Technische Universität München, München, Germany (H.S.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S.); and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (B.Z.).
² From the National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (T.H., R.J., P.C., A.D.J., C.J.O., D.L.); The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (T.H., R.J., P.C., D.L.); Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (A.D.J., C.J.O.); Department of Mathematics and Statistics, Boston University, MA (J.R., M.G.L.); Department of Medicine, University of Massachusetts Medical School, Worcester (K.T., D.D.M., J.E.F.); Department of Integrative Biology and Physiology, University of California, Los Angeles (Q.M., A.B., X.Y.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M); Department of Medicine, Harvard Medical School, Harvard University, Boston, MA (R.J.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.); Departments of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario, Canada (R.M.); Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom; Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (J.E.); DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (J.E.); Deutsches Herzzentrum München, Technische Universität München, München, Germany (H.S.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S.); and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (B.Z.). jane.freedman@umassmed.edu Levyd@nih.gov xyang123@ucla.edu.

Abstract

Objective: The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls.

Approach and results: At false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases versus controls (80% versus 30%; P<1×10(-16)), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the dysregulation of B-cell centered immune function.

Conclusions: Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight coexpression with mRNAs.

Keywords: coronary disease; genetics; systems biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Case-Control Studies
Coronary Disease / blood
Coronary Disease / diagnosis
Coronary Disease / genetics*
Databases, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation
Genetic Association Studies
Genetic Markers
Genetic Predisposition to Disease
Genomics* / methods
Humans
Linear Models
Male
MicroRNAs / blood
MicroRNAs / genetics*
Middle Aged
Oligonucleotide Array Sequence Analysis
Phenotype
Polymorphism, Single Nucleotide
RNA, Messenger / blood
RNA, Messenger / genetics
Reproducibility of Results
Systems Biology

Substances

Genetic Markers
MicroRNAs
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding